The site of the Media Sphera Publishers contains materials intended solely for healthcare professionals.
By closing this message, you confirm that you are a certified medical professional or a student of a medical educational institution.

Login
EN
+7 (495) 482-4118
+7 (495) 482-4329
+8 800 250-18-12
  • (toll-free number for subscriptions)
    Mon-Fri from 10 a.m. to 6 p.m.

  • © 1998-2026
+7 (495) 482-43-29
EN
All journals
Journal
Year
Year
Search result: 0

Nevinitsyna T.A.

FGBU "NII glaznykh bolezneĭ"

Sheremet N.L.

FGBU "NII glaznykh bolezneĭ" RAMN

Molecular mechanisms and pathogenetic treatment of mitochondrial optic neuropathies

Authors:

Nevinitsyna T.A., Sheremet N.L.

More about the authors

Journal: Russian Annals of Ophthalmology. 2016;132(1): 91‑96

DOI: 10.17116/oftalma2016132191-96

Read: 1921 times

Download PDF (RU)
Contact the author
Table of contents

MOLECULAR MECHANISMS AND PATHOGENETIC TREATMENT OF MITOCHONDRIAL OPTIC NEUROPATHIES
MOLECULAR MECHANISMS AND PATHOGENETIC TREATMENT OF MITOCHONDRIAL OPTIC NEUROPATHIES

To cite this article:

Nevinitsyna TA, Sheremet NL. Molecular mechanisms and pathogenetic treatment of mitochondrial optic neuropathies. Russian Annals of Ophthalmology. 2016;132(1):91‑96. (In Russ.)
https://doi.org/10.17116/oftalma2016132191-96

Подписка 2026 Вестник офтальмологии (Russian Annals of Ophthalmology)
МСФ на ЯМ
Использование инфографики авторами научных работ
Close metadata
Recommended articles:
Hybrid wound coating in reha­bilitation of severe thermal burns. (An expe­rimental study). Problems of Balneology, Physiotherapy and Exercise Therapy. 2024;(6-2):40-49
Effi­ciency of a new method of allo­plasty with dermal equivalent with cultured allo­fibroblasts and with the support of poly­deoxyribonucleotides of an ischemic skin defect. Russian Journal of Operative Surgery and Clinical Anatomy. 2025;(1):22-28
Impact of collagen-containing drug on the number and proliferative acti­vity of dermal fibroblasts in the expe­riment. Russian Journal of Clinical Dermatology and Vene­reology. 2025;(5):584-587
The fundamental foundations of periodontal aging. Part 3. Russian Journal of Operative Surgery and Clinical Anatomy. 2025;(4):68-74
Spiny mice (Acomys): a novel and perspective model for research of heart rege­neration and deve­lopment of rege­nerative technologies. Russian Cardiology Bulletin. 2025;(4):10-17
Abstract:

The article presents a review of literature on inherited optic neuropathies (ION), namely, Leber`s hereditary optic neuropathy and autosomal dominant optic neuropathy. Their molecular genetic characteristics and pathogenetic mechanisms such as mitochondrial respiratory chain deficiency, oxidative stress, mitochondrial dynamics, and biogenesis are covered. Prospects of ION treatment are described.

Keywords:

DOA
LHON
mtDNA mutation
OPA1
fibroblasts

Authors:

Nevinitsyna T.A.

FGBU "NII glaznykh bolezneĭ"

Sheremet N.L.

FGBU "NII glaznykh bolezneĭ" RAMN

Close metadata

References:

  1. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dysfunction as a cause of optic neuropathies. Prog Retin Eye Res. 2004;23(1):53-89. doi:10.1016/j.preteyeres.2003.10.003.
  2. Man PYW, Griffiths PG, Brown DT, Howell N, Turnbull DM, Chinnery PF. The epidemiology of Leber hereditary optic neuropathy in the North East of England. Am J Hum Genet. 2003;72(2):333-339.  doi:10.1086/346066.
  3. Spruijt L, Kolbach DN, de Coo RF, Plomp AS, Bauer NJ, Smeets HJ, de Die-Smulders CE. Influence of mutation type on clinical expression of Leber hereditary optic neuropathy. Am J Ophthalmol. 2006;141(4):676-682.  doi:10.1016/j.ajo.2005.11.007.
  4. Puomila A, Hämäläinen P, Kivioja S, Savontaus ML, Koivumäki S, Huoponen K, Nikoskelainen E. Epidemiology and penetrance of Leber hereditary optic neuropathy in Finland. Eur J Human Genet. 2007;15(10):1079-1089. doi:10.1038/sj.ejhg.5201828.
  5. Yu-Wai-Man P, Griffiths PG, Burke A, Sellar PW, Clarke MP, Gnanaraj L, Ah-Kine D, Hudson G, Czermin B, Taylor RW, Horvath R, Chinnery PF. The prevalence and natural history of dominant optic atrophy due to OPA1 mutations. Ophthalmology. 2010;117(8):1538-1546, 1546.e1.  doi:10.1016/j.ophtha.2009.12.038.
  6. Kjer B, Eiberg H, Kjer P, Rosenberg T. Dominant optic atrophy mapped to chromosome 3q region. II. Clinical and epidemiological aspects. Acta Ophthalmol Scand. 1996;74(1):3-7.
  7. Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science. 1988;242(4884):1427-1430. doi:10.1126/science.3201231.
  8. http://www.mitomap.org/bin/view.pl/MITOMAP/MutationsLHON.
  9. Yen MY, Lee HC, Liu JH, Wei YH. Compensatory elevation of complex II activity in Leber’s hereditary optic neuropathy. Br J Ophthalmol. 1996;80(1):78-81.  doi:10.1136/bjo.80.1.78.
  10. Yen MY, Chen CS, Wang AG, Wei YH. Increase of mitochondrial DNA in blood cells of patients with Leber’s hereditary optic neuropathy with 11778 mutation. Br J Ophthalmol. 2002;86(9):1027-1030. doi:10.1136/bjo.86.9.1027.
  11. Nishioka T, Soemantri A, Ishida T. mtDNA/nDNA ratio in 14484 LHON mitochondrial mutation carriers. J Hum Genet. 2004;49(12):701-705.  doi:10.1007/s10038-004-0209-5.
  12. Giordano C, Montopoli M, Perli E, Orlandi M, Fantin M, Ross-Cisneros FN, Caparrotta L, Martinuzzi A, Ragazzi E, Ghelli A, Sadun AA, d’Amati G, Carelli V. Oestrogens ameliorate mitochondrial dysfunction in Leber’s hereditary optic neuropathy. Brain. 2011;134(Pt 1):220-234.  doi:10.1093/brain/awq276.
  13. Giordano C, Iommarini L, Giordano L, Maresca A, Pisano A, Valentino ML, Caporali L, Liguori R, Deceglie S, Roberti M, Fanelli F, Fracasso F, Ross-Cisneros FN, D’Adamo P, Hudson G, Pyle A, Yu-Wai-Man P, Chinnery PF, Zeviani M, Salomao SR, Berezovsky A, Belfort R Jr, Ventura DF, Moraes M, Moraes Filho M,Barboni P, Sadun F, De Negri A, Sadun AA, Tancredi A, Mancini M, d’Amati G, Loguercio Polosa P, Cantatore P, Carelli V. Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy. Brain. 2014;137(Pt 2):335-353. doi:10.1093/brain/awt343.
  14. McKenzie M. Mitochondrial DNA mutations and their effects on complex i biogenesis: implications for metabolic disease. Mitochondrial DNA, mitochondria, disease and stem cells. Humana Press; 2012:25-47. doi:10.1007/978-1-62703-101-1_2.
  15. Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet. 2001;2(5):342-352. doi:10.1038/35072063.
  16. Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE. Bovine Complex I Is a Complex of 45 Different Subunits. J Biol Chem. 2006;281(43):32724-32727. doi:10.1074/jbc.m607135200.
  17. Baracca A, Solaini G, Sgarbi G, Lenaz G, Baruzzi A, Schapira AH, Martinuzzi A, Carelli V. Severe impairment of complex i-driven adenosine triphosphate synthesis in leber hereditary optic neuropathy cybrids. Arch Neurol. 2005;62(5):730-736.  doi:10.1001/archneur.62.5.730.
  18. Chevrollier A, Guillet V, Loiseau D, Gueguen N, de Crescenzo MA, Verny C, Ferre M, Dollfus H, Odent S, Milea D, Goizet C, Amati-Bonneau P, Procaccio V,Bonneau D, Reynier P. Hereditary optic neuropathies share a common mitochondrial coupling defect. Ann Neurol. 2008;63(6):794-798. doi:10.1002/ana.21385.
  19. Zanna C, Ghelli A, Porcelli AM, Karbowski M, Youle RJ, Schimpf S, Wissinger B, Pinti M, Cossarizza A, Vidoni S, Valentino ML, Rugolo M, Carelli V. OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion. Brain. 2008;131(Pt 2):352-367.  doi:10.1093/brain/awm335.
  20. Lodi R, Taylor DJ, Tabrizi SJ, Kumar S, Sweeney M, Wood NW, Styles P, Radda GK, Schapira AH. In vivo skeletal muscle mitochondrial function in Leber’s hereditary optic neuropathy assessed by 31P magnetic resonance spectroscopy. Ann Neurol. 1997;42(4):573-579. doi:10.1002/ana.410420407.
  21. Lodi R, Tonon C, Valentino ML, Manners D, Testa C, Malucelli E, La Morgia C, Barboni P, Carbonelli M, Schimpf S, Wissinger B, Zeviani M, Baruzzi A, Liguori R, Barbiroli B, Carelli V. Defective mitochondrial adenosine triphosphate production in skeletal muscle from patients with dominant optic atrophy due to OPA1 mutations. Arch Neurol. 2011;68(1):67-73.  doi:10.1001/archneurol.2010.228.
  22. Chance B, Boveris A, Nakase Y, Sies H. Hydroperoxide metabolism: An overview. In: Functions of glutathione in liver and kidney. Sies H, Wendel A, eds. New York: Springer; 1978:95-106.  doi:10.1007/978-3-642-67132-6_12.
  23. Lenaz G. Role of mitochondria in oxidative stress and ageing. Biochim Biophys Acta. 1998;1366(1-2):53-67.  doi:10.1016/s0005-2728(98)00120-0.
  24. Yu BP. Cellular defenses against damage from reactive oxygen species. Physiol Rev. 1994;74(1):139-162.
  25. Koopman WJ, Nijtmans LG, Dieteren CE, Roestenberg P, Valsecchi F, Smeitink JA, Willems PH. Mammalian mitochondrial complex I: biogenesis, regulation, and reactive oxygen species generation. Antioxid Redox Signal. 2010;12(12):1431-1470. doi:10.1089/ars.2009.2743.
  26. Handy DE, Loscalzo J. Redox regulation of mitochondrial function. Antioxid Redox Signal. 2012;16(11):1323-1367. doi:10.1089/ars.2011.4123.
  27. Ban T, Heymann JAW, Song Z, Hinshaw JE, Chan DC. OPA1 disease alleles causing dominant optic atrophy have defects in cardiolipin-stimulated GTP hydrolysis and membrane tubulation. Hum Mol Genet. 2010;19(11):2113-2122. doi:10.1093/hmg/ddq088.
  28. Brown MD. The enigmatic relationship between mitochondrial dysfunction and Leber’s hereditary optic neuropathy. J Neurol Sci. 1999;165(1):1-5. doi:10.1016/s0022-510x(99)00087-8.
  29. Beretta S, Mattavelli L, Sala G, Tremolizzo L, Schapira AH, Martinuzzi A, Carelli V, Ferrarese C. Leber hereditary optic neuropathy mtDNA mutations disrupt glutamate transport in cybrid cell lines. Brain. 2004;127(10):2183-2192. doi:10.1093/brain/awh258.
  30. Wong A, Cavelier L, Collins-Schramm HE, Seldin MF, McGrogan M, Savontaus ML, Cortopassi GA. Differentiation-specific effects of LHON mutations introduced into neuronal NT2 cells. Hum Mol Genet. 2002;11(4):431-438. doi:10.1093/hmg/11.4.431.
  31. Yarosh W, Monserrate J, Tong JJ, Tse S, Le PK, Nguyen K, Brachmann CB, Wallace DC, Huang T. The molecular mechanisms of OPA1-mediated optic atrophy in drosophila model and prospects for antioxidant treatment. PLoS Genet. 2008;4(1):e6. doi:10.1371/journal.pgen.0040006.
  32. Fontaine E, Eriksson O, Ichas F, Bernardi P. Regulation of the permeability transition pore in skeletal muscle mitochondria. Modulation by electron flow through the respiratory chain complex I. J Biol Chem. 1998;273(20):12662-12668. doi:10.1074/jbc.273.20.12662.
  33. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of Apoptosis by Bcl-2: Release of Cytochrome c from Mitochondria Blocked. Science. 1997;275(5303):1129-1132. doi:10.1126/science.275.5303.1129.
  34. Olichon A. Loss of OPA1 Perturbates the Mitochondrial Inner Membrane Structure and Integrity, Leading to Cytochrome c Release and Apoptosis. J Biol Chem. 2002;278(10):7743-7746. doi:10.1074/jbc.c200677200.
  35. Smith KJ, Kapoor R, Felts PA. Demyelination: the role of reactive oxygen and nitrogen species. BrainPathol. 1999;9(1):69-92. doi:10.1111/j.1750-3639.1999.tb00212.x.
  36. Carelli V, Ross-Cisneros FN, Sadun AA. Optic nerve degeneration and mitochondrial dysfunction: genetic and acquired optic neuropathies. Neurochem Int. 2002;40(6):573-584. doi:10.1016/s0197-0186(01)00129-2.
  37. Hermann GJ, Thatcher JW, Mills JP, Hales KG, Fuller MT, Nunnari J, Shaw JM. Mitochondrial fusion in yeast requires the transmembrane GTPase Fzo1p. J Cell Biol. 1998;143(2):359-373. doi:10.1083/jcb.143.2.359.
  38. Chen H, McCaffery JM, Chan DC. mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007;130(3):548-562. doi:10.1016/j.cell.2007.06.026.
  39. Parone PA, Da Cruz S, Tondera D, Mattenberger Y, James DI, Maechler P, Barja F, Martinou JC. Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS One. 2008;3(9):e3257. doi:10.1371/journal.pone.0003257.
  40. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 2009;43(1):67-93. doi:10.1146/annurev-genet-102808-114910.
  41. Wallace DC. A mitochondrial paradigm for degenerative diseases and ageing. Novartis Found Symp. 2001;235:247-266. doi:10.1002/0470868694.ch20.
  42. Lemasters JJ. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. RejuvenationRes. 2005;8(1):3-5. doi:10.1089/rej.2005.8.3.
  43. Kim I, Rodriguez-Enriquez S, Lemasters JJ. Selective degradation of mitochondria by mitophagy. Arch Biochem Biophys. 2007;462(2):245-253. doi:10.1016/j.abb.2007.03.034.
  44. Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 2008;27(2):433-446. doi:10.1038/sj.emboj.7601963.
  45. Olichon A, Landes T, Arnauné-Pelloquin L, Emorine LJ, Mils V, Guichet A, Delettre C, Hamel C, Amati-Bonneau P, Bonneau D, Reynier P, Lenaers G, Belenguer P. Effects of OPA1 mutations on mitochondrial morphology and apoptosis: relevance to ADOA pathogenesis. J Cell Physiol. 2007;211(2):423-430. doi:10.1002/jcp.20950.
  46. Diaz F, Moraes CT. Mitochondrial biogenesis and turnover. Cell Calcium. 2008;44(1):24-35. doi:10.1016/j.ceca.2007.12.004.
  47. Carta A, Carelli V, D’Adda T, Ross-Cisneros FN, Sadun AA. Human extraocular muscles in mitochondrial diseases: comparing chronic progressive external ophthalmoplegia with Leber’s hereditary optic neuropathy. Br J Ophthalmol. 2005;89(7):825-827. doi:10.1136/bjo.2004.060590.
  48. Valentino ML, Barboni P, Ghelli A, Bucchi L, Rengo C, Achilli A, Torroni A, Lugaresi A, Lodi R, Barbiroli B, Dotti M, Federico A, Baruzzi A, Carelli V. The ND1 gene of complex I is a mutational hot spot for Leber’s hereditary optic neuropathy. Ann Neurol. 2004;56(5):631-641. doi:10.1016/j.ajo.2004.12.044.
  49. Robinson BH, Petrova-Benedict R, Buncic JR, Wallace DC. Nonviability of cells with oxidative defects in galactose medium: a screening test for affected patient fibroblasts. Biochem Med Metab Biol. 1992;48(2):122-126.  doi:10.1016/0885-4505(92)90056-5.
  50. Cornelissen JC, Wanders RJ, Bolhuis PA, Bleeker-Wagemakers E, Oostra RJ, Wijburg FA. Respiratory chain function in Leber’s hereditary optic neuropathy: lack of correlation with clinical disease. J Inherit Metab Dis. 1993;16(3):531-533. doi:10.1007/bf00711673.
  51. Amati-Bonneau P, Valentino ML, Reynier P, Gallardo ME, Bornstein B, Boissière A, Campos Y, Rivera H, de la Aleja JG, Carroccia R, Iommarini L, Labauge P, Figarella-Branger D, Marcorelles P, Furby A, Beauvais K, Letournel F, Liguori R, La Morgia C, Montagna P, Liguori M, Zanna C, Rugolo M, Cossarizza A, Wissinger B, Verny C, Schwarzenbacher R, Martín MA, Arenas J, Ayuso C, Garesse R, Lenaers G, Bonneau D, Carelli V. OPA1 mutations induce mitochondrial DNA instability and optic atrophy ‘plus’ phenotypes. Brain. 2008;131(Pt 2):338-351. doi:10.1093/brain/awm298.
  52. Saada A. The use of individual patient’s fibroblasts in the search for personalized treatment of nuclear encoded OXPHOS diseases. Mol Genet Metab. 2011;104(1-2):39-47. doi:10.1016/j.ymgme.2011.07.016.
  53. Sheremet N.L., Khanakova N.A., Nevinitsyna T.A., Tsygankova P.G., Itkis Yu.S., Krylova T.D., Loginova A.N., Chukhrova A.L., Venkova L.S., Svistunova D.M., Chernoivanenko I.S., Zakharova E.Yu., Polyakov A.V., Minin A.A. Sovremennye vozmozhnosti i perspektivy izucheniya patogeneza, diagnostiki i lecheniya nasledstvennykh opticheskikh neiropatii. Vestnik oftal'mologii. 2014;6:62-70.
  54. Bonnet C, Augustin S, Ellouze S, Bénit P, Bouaita A, Rustin P, Sahel JA, Corral-Debrinski M. The optimized allotopic expression of ND1 or ND4 genes restores respiratory chain complex I activity in fibroblasts harboring mutations in these genes. Biochim Biophys Acta. 2008;1783(10):1707-1717. doi:10.1016/j.bbamcr.2008.04.018.
  55. Saada A. Mitochondria: mitochondrial OXPHOS (dys) function ex vivo — the use of primary fibroblasts. Int J Biochem Cell Biol. 2014;48:60-65. doi:10.1016/j.biocel.2013.12.010.
  56. Sadun AA, Morgia C, Carelli V. Leber’s Hereditary Optic Neuropathy. Curr Treat Options Neurol. 2010;13(1):109-117.  doi:10.1007/s11940-010-0100-y.
  57. Guy J, Qi XP, Pallotti F, Schon EA, Manfredi G, Carelli V, Martinuzzi A, Hauswirth WW, Lewin AS. Rescue of a mitochondrial deficiency causing Leber Hereditary Optic Neuropathy. Ann Neurol. 2002;52(5):534-542. doi:10.1002/ana.10354.
  58. Cwerman-Thibault H, Augustin S, Ellouze S, Sahel J-A, Corral-Debrinski M. Gene therapy for mitochondrial diseases: Leber Hereditary Optic Neuropathy as the first candidate for a clinical trial. C R Biol. 2014;337(3):193-206. doi:10.1016/j.crvi.2013.11.011.
  59. https://clinicaltrials.gov/ct2/results?term=lhon&Search=Search.
  60. Newman NJ. Treatment of hereditary optic neuropathies. Nat Rev Neurol. 2012;8(10):545-556.  doi:10.1038/nrneurol.2012.167.
  61. Klopstock T, Yu-Wai-Man P, Dimitriadis K, Rouleau J, Heck S, Bailie M, Atawan A, Chattopadhyay S, Schubert M, Garip A, Kernt M, Petraki D, Rummey C, Leinonen M, Metz G, Griffiths PG, Meier T, Chinnery PF. A randomized placebo-controlled trial of idebenone in Leber’s hereditary optic neuropathy. Brain. 2011;134(Pt 9):2677-2686. doi:10.1093/brain/awr170.
  62. Sadun AA, Chicani CF, Ross-Cisneros FN, Barboni P, Thoolen M, Shrader WD, Kubis K, Carelli V, Miller G. Effect of EPI-743 on the clinical course of the mitochondrial disease Leber hereditary optic neuropathy. Arch Neurol. 2012;69(3):331-338. doi:10.1001/archneurol.2011.2972.
  63. Dai Y, Zheng K, Clark J, Swerdlow RH, Pulst SM, Sutton JP, Shinobu LA, Simon DK. Rapamycin drives selection against a pathogenic heteroplasmic mitochondrial DNA mutation. Hum Mol Genet. 2013;23(3):637-647. doi:10.1093/hmg/ddt450.
Contact the author
Email
Message
The publishing house "Media Sphere" does not provide treatment services, does not give recommendations on contacting medical institutions and specific specialists, on the prescription of medicines and dietary supplements.

Email Confirmation

An email was sent to test@gmail.com with a confirmation link. Follow the link from the letter to complete the registration on the site.

Email Confirmation

Contact us
If you have any questions, complaints or suggestions, please use this feedback form.
Email
Message
The publishing house "Media Sphere" does not provide treatment services, does not give recommendations on contacting medical institutions and specific specialists, on the prescription of medicines and dietary supplements.
Submit Application

You can become an author of one of our magazines, send a request and we will consider it in during the day.

Name
Phone
E-mail
Message
Login
Registration
E-mail
Password
Forgot Password?

Log in to the site using your account in one of the services

Password recovery
E-mail
Login
Register

We use cооkies to improve the performance of the site. By staying on our site, you agree to the terms of use of cооkies. To view our Privacy and Cookie Policy, please. click here.